Our long-term objective is to improve outcomes for pediatric liver transplant recipients with discoveries to guide clinical decision-making related to immunosuppression management in general and immunosuppression minimization and/or withdrawal in specific. In 2007, an NIH-sponsored consensus conference on long-term outcomes in pediatric liver transplantation concluded that (1) long-term immunosuppression precipitates substantial non-immune and immune-related complications and that (2) identification of biomarkers that inform immunologic mechanisms of tolerance would lessen the risk for complications and lead to intervention studies to individualize, minimize, and/or withdraw immunosuppression. The conclusion of the consensus conference is strongly aligned with the NIAID mission in transplant immunology to conduct clinical trials to evaluate approaches that include tolerogenic, anti-inflammatory, and immunomodulatory strategies to treat and prevent immune-mediated diseases and to explore the mechanisms of action of such approaches. To directly address the challenges put forth at the consensus conference and by NIAID, we will conduct a multi-center, single arm, prospective, longitudinal study to test the hypothesis that a defined subset of pediatric liver transplant recipients can safely and durably withdraw from immunosuppression (Aim 1). The primary endpoint will be the proportion of participants who are operationally tolerant, defined as those who successfully withdraw from immunosuppression and maintain normal allograft status, assessed by liver biopsy and liver tests, 12 months after the last immunosuppression dose. We will conduct an extensive battery of translational studies, engaging research teams within and outside the Immune Tolerance Network, the goal of which is to identify and validate a cross- platform biomarker predictive of operational tolerance (Aim 2) The current study provides an innovative and comprehensive approach, bringing together clinical experts, leaders in transplant pathology and leaders in transplant immunology to address critical gaps in knowledge. The expected outcome of the study will be the identification of a clinical phenotype of operational tolerance that will enable us to derive and validate a cross platform - clinical, histological, transcriptional, and/or immunologic - biomarker predictive of operational tolerance, and in doing so, substantially alter the long-term immunosuppression management of stable pediatric liver transplantation. PUBLIC HEALTH RELEVANCE: The objectives of the application are to assess the efficacy of immunosuppression withdrawal for stable pediatric liver transplant recipients and to identify a cross-platform biomarker predictive of operational tolerance. The knowledge gained will redefine clinical practice, freeing targeted patients from the morbidity associated with chronic, lifelong immunosuppression.